It is well established that hepatic cirrhosis results in reduced clearance of drugs that are highly metabolized and an enhanced sensitivity to the pharmacological and adverse actions of drugs. Chronic alcohol consumption and hepatitis C are the two most common causes of cirrhosis in the United States with an incidence of 3.1 per 1000 people. The development of portal hypertension is the primary mechanism behind several major complications of cirrhosis such as bleeding from gastroesophageal varices, hepatic encephalopathy, and ascites. Transjugular intrahepatic portosystemic shunts (TIPS) and other surgical shunts are performed to manage these complications of portal hypertension. We have demonstrated that in addition to a reduction in hepatic clearance, cirrhotic patients with TIPS experience an increase in intestinal availability of midazolam, a selective cytochrome P450 3A (CYP3A) substrate. This increased bioavailability primarily reflects a functional lack of intestinal wall first-pass metabolism relative to cirrhotics without TIPS and healthy volunteers. The mechanism for this lack of intestinal wall metabolism is unknown. We propose to characterize the mechanism and consequences of this loss of intestinal wall CYP3A activity in cirrhotics with TIPS by directly examining the CYP3A protein and mRNA levels, intestinal permeability, and in vivo hepatic and intestinal CYP3A activity before, immediately after, and I month after TIPS placement. Cirrhotic patients with TIPS, and potentially other types of portosystemic shunts, are expected to be at risk for excessive pharmacological effects or suffer from an increased incidence of adverse reactions following CYP3A substrate administration. We will examine the susceptibility of these individuals to adverse drug reactions and drug-drug interaction by examining the ability of erythromycin to prolong the QT interval and clarithromycin to inhibit metabolism of buspirone, a CYP3A substrate. Finally, the expression of other enzymes such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs) and p-glycoprotein may also be altered in cirrhosis. We will characterize the changes in these enzymes using the partial clearance of acetaminophen to glucuronide (UGT) and sulfate (SULT) conjugates and the disposition of fexofenadine in cirrhotics with and without TIPS and healthy volunteers.